Amplified RPS6KB1 and CDC2 Are Potential Biomarkers for Aggressive Large B-Cell Lymphomas in HIV Patients
X Frank Zhao, Merry Y Zhao, Ling Cai, Debra Kukuruga, Ming Tan, Sanford A Stass. University of Maryland School of Medicine, Baltimore, MD
Background: RPS6KB1 encodes p70S6K/p85S6K, a serine/threonine protein kinase that plays key roles in the PI3K/Akt/mTOR signal transduction pathway. CDC2 encodes cdc2, a serine/threonine protein kinase that is critical for M/G2 cell cycle progression. We have shown that RPS6KB1 and CDC2 genes were amplified in some diffuse large B-cell lymphomas (DLBCL), and their products p70S6K/p85S6K and cdc2 were potential therapeutic targets for combination therapy. Moreover, amplified RPS6KB1 and CDC2 were detected in the EBV+ DLBCL of HIV patients. In this study, we further evaluate these genes in DLBCLs from a cohort of patients with HIV infection.
Design: With IRB approval, we collected 12 HIV-related DLBCLs from the 2005-2009 pathology archives of University of Maryland Medical Center, with 10 cases of non-HIV-related DLBCLs. The cases were divided into 4 groups: 1) EBV- DLBCL from HIV-negative patients (HIV-/EBV-); 2) EBV+ DLBCL from HIV-negative patients (HIV-/EBV+); 3) EBV- DLBCL from HIV+ patients; 4) EBV+ DLBCL from HIV+ patients. Ten samples of paraffin-embedded CNS DLBCL and non-lymphoma tissues from HIV+ patients were obtained from the NCI AIDS and Cancer Specimen Resource (ACSR). DNA was prepared from each paraffin embedded specimen and analyzed using real time quantitative PCR.
Results: Three groups (HIV-/EBV-, HIV-/EBV+, and HIV+/EBV-) were lumped to form a non-HIV+/EBV+ group. The results showed the amplified RPS6KB1 and CDC2 were highly positively correlated (estimated Pearson's correlation coefficient is 0.95). Receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to assess the ability of each gene to distinguish non-HIV+/EBV+ cases from HIV+/EBV+ cases. The AUC was estimated to be 0.76 (Std=0.13) for RPS6KB1 and 0.74 (Std=0.13) for CDC2, respectively, by using the Mann–Whitney statistic. The amplified gene levels were higher in the CNS DLBCLs than in the non-lymphoma tissues for both RPS6KB1 (p=0.001) and CDC2 (p=0.019). Pathology revealed the amplified RPS6KB1 and CDC2 were frequently associated with immunoblastic, anaplastic, and plasmablastic variants of DLBCL, and primary CNS DLBCL, which are more commonly seen in patients with HIV infection.
Conclusions: Taken together, amplified RPS6KB1 and CDC2 are potential biomarkers for aggressive DLBCLs, particularly in patients with HIV and EBV infections. These results were validated in the CAP/CLIA-certified University of Maryland Biomarker Reference Laboratory.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 194, Tuesday Afternoon